The present invention relates to a production method of an optically active xcex2-amino-xcex1-hydroxycarboxylic acid. Additionally, the present invention relates to a production method of an optically active N-carbamate type protected xcex2-amino-xcex1-hydroxycarboxylic acid.
xcex2-Amino-xcex1-hydroxycarboxylic acid of the formula (1) 
wherein A is alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms or aralkyl group having 7 to 20 carbon atoms, each optionally having substituent(s) and optionally having heteroatom(s) in the carbon skeleton, and * shows an asymmetric carbon atom, is known to be useful as an intermediate for HIV protease inhibitors, carcinostatics and the like (see, for example, B. Munoz et al., Bioorg. Med. Chem., 1994, 2 (10), 1085, R. Nishizawa et al., J. Med. Chem., 1977, 20 (4), 510).
Furthermore, as the production method of xcex2-amino-xcex1-hydroxycarboxylic acid of the formula (1), for example, a production method shown by Scheme 1 in J. Med. Chem., 1977, 20 (4), 510 is known. 
According to the above-mentioned method, however, highly toxic potassium prussiate needs to be used. Moreover, this method shows poor stereoselectivity, and the xcex2-amino-xcex1-hydroxycarboxylic acid is obtained as a diastereomeric mixture. Accordingly, this method is not necessarily an industrially suitable production method.
As a production method of xcex2-amino-xcex1-hydroxycarboxylic acid derivative, moreover, a production method shown by Scheme 2 in Synlett, 1996, 6, 585 is known. 
The above-mentioned method requires expensive ruthenium catalyst, caesium carbonate, and also explosive sodium periodate. Accordingly, this production method is not necessarily an industrially suitable production method.
Accordingly, the present invention aims at providing industrial methods of producing an optically active xcex2-amino-xcex1-hydroxycarboxylic acid and an optically active N-carbamate type protected xcex2-amino-xcex1-hydroxycarboxylic acid.
The present inventors have intensively studied in an attempt to solve the aforementioned problems and obtained a specific xcex2-amino-xcex1-hydroxycarboxylic acid by reacting an N-carbamate type protected xcex2-aminoepoxide with an acid to give specific 5-hydroxymethyl-oxazolidin-2-one, which is oxidized in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (hereinafter sometimes to be abbreviated as TEMPO) and hypochlorite to give a specific 2-oxo-5-oxazolidinecarboxylic acid, which is then reacted with a base. Furthermore, they have found that a series of reactions proceed stereoselectively to produce the objective compound having a high optical purity in a high yield.
The present invention is based on such findings and provides the following.
A production method of xcex2-amino-xcex1-hydroxycarboxylic acid of the formula (1) 
wherein A is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, each optionally having substituent(s) and optionally having heteroatom(s) in the carbon skeleton, and * shows an asymmetric carbon atom, provided that, when the configuration of the 2-position and 3-position of xcex2-amino-xcex1-hydroxycarboxylic acid of the formula (1) is (2R,3S), (2S,3R), (2S,3S) or (2R,3R), the configuration of the 2-position and 3-position of N-carbamate protected xcex2-aminoepoxide of the following formula (2) is (2S,3S), (2R,3R) (2R,3S) or (2S,3R), respectively, the configuration of the 4-position and 5-position of the oxazolidin-2-one derivative of the following formula (3) is (4S, 5R), (4R, 5S), (4S, 5S) or (4R, 5R) respectively, and the configuration of the 4-position and 5-position of oxazolidin-2-one derivative of the following formula (4) is (4S, 5R), (4R, 5S), (4S, 5S) or (4R, 5R), respectively: which method comprises the following steps (a)-(c)
(a) treating an N-carbamate protected xcex2-aminoepoxide of the formula (2) 
wherein R1 is a tert-butyl group or a benzyl group, and A and * are as defined above, with an acid to give an oxazolidin-2-one derivative of the formula (3) 
wherein A and * are as defined above,
(b) oxidizing the oxazolidin-2-one derivative of the formula (3) in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy and hypochlorite to give an oxazolidin-2-one derivative of the formula (4) 
wherein A and * are as defined above,
(c) treating the oxazolidin-2-one derivative of the formula (4) with a base to give the xcex2-amino-xcex1-hydroxycarboxylic acid of the formula (1).
A production method of an N-carbamate protected xcex2-amino-xcex1-hydroxycarboxylic acid of the formula (5) 
wherein R2 is a lower alkyl group, a benzyl group or a fluorenylmethyl group, * shows an asymmetric carbon atom and A is as defined above, which method comprises obtaining xcex2-amino-xcex1-hydroxycarboxylic acid of the formula (1) according to the above-mentioned production method, and protecting an amino group of the xcex2-amino-xcex1-hydroxycarboxylic acid with a carbamate type protecting group, provided that when the configuration of the 2-position and 3-position of the xcex2-amino-xcex1-hydroxycarboxylic acid of the formula (1) is (2R,3S), (2S,3R), (2S,3S) or (2R,3R), the configuration of the 2-position and 3-position of the N-carbamate protected xcex2-amino-xcex1-hydroxycarboxylic acid of the formula (5) is (2R,3S), (2S,3R), (2S,3S) or (2R,3R), respectively.
The present invention is explained in detail in the following.
In the formulas of the present invention, A is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, each optionally having substituent(s) and optionally having heteroatom(s) in the carbon skeleton, or a hydrogen atom. When A has a substituent, the substituent is free of any particular limitation as long as it does not adversely affect the reaction in the present invention. For example, alkoxy group (preferably having 1 to 7 carbon atoms), nitro group, alkyl group (preferably having 1 to 7 carbon atoms), halogen group and the like are mentioned.
The group containing a heteroatom (nitrogen, oxygen atom and the like) in the carbon skeleton is exemplified by 4-benzyloxyphenylmethyl group and the like.
Such group can be introduced using an amino acid as a starting material. For example, when A is a methyl group, alanine is used, when it is an isopropyl group, valine is used, when it is a 2-methylpropyl group, leucine is used, when it is a 1-methylpropyl group, isoleucine is used, when it is a benzyl group, phenylalanine is used, when it is a cyclohexylmethyl group, cyclohexylalanine is used, and when it is a phenyl group, phenylglycine is used as a starting material for the introduction.
In addition, A may be a group introduced by the use, as a starting material, of an amino acid having a protected functional group of the side chain of the amino acid, such as 0-benzyl tyrosine and the like.
Furthermore, A is not limited to a group introduced from a starting material derived from a natural amino acid, and may be a group introduced from a starting material derived from a non-natural amino acid (e.g., phenyl group, cyclohexylmethyl group).
A is particularly preferably a benzyl group.
In the formulas of the present invention, R1 is a tert-butyl group or a benzyl group. R1 is particularly preferably a tert-butyl group.
In the formulas of the present invention, R2 is a lower alkyl group, a benzyl group or a fluorenylmethyl group. The lower alkyl group is an alkyl group having 1 to 8 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms. For example, methyl group, ethyl group, tert-butyl group and the like are mentioned. R2 is particularly preferably a tert-butyl group.
The N-carbamate type protected xcex2-aminoepoxide of the formula (2) used as a starting material in the present invention is a known compound and can be produced by a known method comprising, for example, reducing N-carbamate type protected a-chloromethyl ketone of the formula (6), and treating with a base, and the like (see, for example, WO00/44706, EP 1081133). 
wherein A is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, each optionally having substituent(s) and optionally having heteroatom(s) in the carbon skeleton, R1 is a tert-butyl group or a benzyl group, and * shows an asymmetric carbon atom.
The production method of the 5-hydroxymethyl-oxazolidin-2-one derivative (formula (3)), which comprises reacting an N-carbamate type protected xcex2-aminoepoxide derivative (formula (2)) with an acid, is explained in the following.
As the acid, for example, a solid acid such as acidic ion-exchange resin (ion-exchange resin acid catalyst), acidic alumina (alumina acid catalyst), acidic zeolite (zeolite acid catalyst), acidic clay and the like, Lewis acid such as boron trifluoride-ether complex and the like, hydrochloric acid, sulfuric acid, acetic acid, citric acid, methanesulfonic acid, para-toluenesulfonic acid and the like are mentioned. As the acidic ion-exchange resin, for example, Amberlyst 15 ion-exchange resin (Amberlyst, registered trademark) (Sigma-Aldrich) and the like are mentioned.
When the configuration of the 2-position and 3-position of N-carbamate type protected xcex2-aminoepoxide is (2S,3S) or (2R,3R), a solid acid such as acidic ion-exchange resin (ion-exchange resin acid catalyst), acidic alumina (alumina acid catalyst), acidic zeolite (zeolite acid catalyst), acidic clay and the like, Lewis acid such as boron trifluoride-ether complex and the like, citric acid, methanesulfonic acid and para-toluenesulfonic acid are preferable, and acidic ion-exchange resin and citric acid are particularly preferable.
When the configuration of the 2-position and 3-position of N-carbamate type protected xcex2-aminoepoxide is (2R,3S) or (2S,3R), a solid acid is less likely to cause side reactions, such as acidic ion-exchange resin (ion-exchange resin acid catalyst), acidic alumina (alumina acid catalyst), acidic zeolite (zeolite acidic catalyst), acidic clay and the like, and Lewis acid such as boron trifluoride-ether complex and the like are preferable.
These acids may be used alone or in combination of one or more kinds thereof.
As a reaction solvent when the configuration of the 2-position and 3-position of N-carbamate type protected xcex2-aminoepoxide is (2S,3S) or (2R,3R), protonic solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, water and the like, and non-protonic solvents such as acetone, 2-butanone, methylisobutylketone, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, toluene and the like are preferably used.
These reaction solvents may be used alone or in combination of one or more kinds thereof.
Particularly, acetonitrile, ethanol or 2-propanol, or a mixed solvent of water and acetonitrile, ethanol or 2-propanol is preferable.
When the configuration of the 2-position and 3-position is (2R,3S) or (2S,3R), a non-protonic solvent, such as acetone, 2-butanone, methylisobutylketone, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, toluene and the like, particularly acetonitrile, is preferable. The use of a protonic solvent when the configuration of the 2-position and 3-position is (2R,3S) or (2S,3R) is not preferable, because it causes side reactions.
These reaction solvents may be used alone or in combination of one or more kinds thereof.
While the amount of acid to be used varies depending on the kind of acid and solvent to be used, it is preferably 1-5 equivalents, more preferably 1-2 equivalents, relative to the compound of the formula (2). While the reaction temperature also varies depending on the kind of acid and solvent used, it is generally from xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably from 20xc2x0 C. to 80xc2x0 C. The reaction temperature may be changed during the reaction. The reaction time is not particularly limited but it is preferably about 10 min to 24 hrs.
The reaction is generally carried out under stirring, and after the completion of the reaction, a base may be added to quench the reaction. Preferable examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like.
Furthermore, by extraction as necessary using a solvent such as dichloromethane, ethyl acetate and the like, and evaporation of the organic solvent(s), 5-hydroxymethyl-oxazolidin-2-one (formula (3)) can be isolated.
The oxidization in the next step may be successively carried out without extraction, or without isolating 5-hydroxymethyl-oxazolidin-2-one. The reaction solvent in this case is acetonitrile, or a mixed solvent of acetonitrile and water is most preferable.
The method for obtaining a 2-oxo-5-oxazolidinecarboxylic acid derivative (formula (4)) by oxidization of 5-hydroxymethyl-oxazolidin-2-one derivative (the formula (3)) in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy and hypochlorite is explained next in the following.
As the solvent, for example, a mixed solvent of a non-protonic solvent such as acetonitrile, dichloromethane, 1, 2-dichloroethane and the like and an aqueous solution is preferably used. In this case, more than one kind of non-protonic solvents may be used in a mixture. The ratio of the non-protonic solvent:aqueous solution is preferably 1:4-20:1.
The aqueous solution to be used in admixture with the non-protonic solvent is preferably pH buffer. The reaction mixture generally has pH 7.0-11.0, particularly preferably 8.0-11.0. The buffer is, for example, sodium phosphate buffer, potassium phosphate buffer, sodium carbonate buffer, potassium carbonate buffer and the like. Sodium carbonate buffer is particularly preferable.
The amount of 2,2,6,6-tetramethyl-1-piperidinyloxy to be used is generally 0.001-0.1 equivalent, preferably 0.001-0.01 equivalent, relative to the compound of the formula (3).
As the hypochlorite, sodium hypochlorite, potassium hypochlorite and the like are mentioned, with particular preference given to sodium hypochlorite.
The amount of hypochlorite to be used is generally 2.0-6.0 equivalents, preferably 2.0-2.5 equivalents, relative to the compound of the formula (3). Hypochlorite may be added at once but it is preferably added dropwise slowly.
Where necessary, potassium bromide, sodium bromide and the like may be added before adding hypochlorite. In this case, the amount of potassium bromide to be used is preferably 0.2-2.5 equivalents relative to the compound of the formula (3). Where necessary, chlorite such as sodium chlorite and the like may be added. In this case, the amount of chlorite to be used is preferably 1.0-2.5 equivalents relative to the compound of the formula (3).
The reaction is generally carried out under stirring and after the completion of the reaction, excess hypochlorite is reduced. As the reductant, for example, sodium thiosulfate, sodium hydrogensulfite and the like are used. The reaction temperature is generally preferably from xe2x88x9210xc2x0 C. to 40xc2x0 C., particularly preferably from xe2x88x9210xc2x0 C. to 20xc2x0 C. The reaction temperature may be changed during reaction. The reaction time is not particularly limited, but it is preferably about 30 min to 24 hrs. after the completion of the dropwise addition.
After adding a reductant, an acid may be added as necessary to adjust the reaction mixture to pH 1.0-4.0 to facilitate the extraction with a solvent such as dichloromethane, ethyl acetate and the like. The acid to be used, for example, hydrochloric acid, sulfuric acid, methanesulfonic acid, para-toluenesulfonic acid and the like are preferably used. After the extraction, the solvent is evaporated to isolate a 2-oxo-5-oxazolidinecarboxylic acid derivative (formula (4)).
Alternatively, the next step for obtaining xcex2-amino-xcex1-hydroxycarboxylic acid (formula (1)) may be successively carried out without extraction, or without isolation of a 2-oxo-5-oxazolidinecarboxylic acid derivative (formula (4)). The solvent to be used in this case is most preferably a mixed solvent of acetonitrile and water.
In the following, a method for obtaining a xcex2-amino-xcex1-hydroxycarboxylic acid derivative (formula (1)) by treating 2-oxo-5-oxazolidinecarboxylic acid derivative (the formula (4)) with a base is explained.
As the base, for example, lithium hydroxide, potassium hydroxide, sodium hydroxide and caesium carbonate, particularly lithium hydroxide and potassium hydroxide, are preferably used.
These bases may be used alone or in combination of one or more kinds thereof.
As the reaction solvent, for example, protonic solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, water and the like, or non-protonic solvents such as acetone, 2-butanone, methylisobutylketone, tetrahydrofuran, 1,4-dioxane, acetonitrile and the like are mentioned.
These solvents may be used alone or in combination of one or more kinds thereof.
Particularly, 2-propanol or a mixed solvent of acetonitrile and water is preferable.
While the amount of the base to be used varies depending on the kind of base and solvent, it is generally 1-10 equivalents, more preferably 1-5 equivalents, relative to the compound of the formula (4). While the reaction temperature also varies depending on the kind of base and solvent used, it is generally from xe2x88x9210xc2x0 C. to 110xc2x0 C., preferably from 20xc2x0 C. to 100xc2x0 C. The reaction temperature may be changed during the reaction. The reaction time is not particularly limited but it is preferably about 30 min to 24 hrs.
The reaction is generally carried out under stirring, and after the completion of the reaction, an acid may be added for crystallization under neutral conditions. The pH in this case is preferably 5.0-8.0, particularly preferably 5.0-7.0. The temperature during crystallization is preferably xe2x88x9210xc2x0 C. to 30xc2x0 C., particularly xe2x88x9210xc2x0 C. to 20xc2x0 C. The acid to be used is, for example, hydrochloric acid, sulfuric acid, acetic acid and citric acid, particularly hydrochloric acid, are preferable.
In addition, a step for obtaining an N-carbamate type protected xcex2-amino-xcex1-hydroxycarboxylic acid derivative (formula (5)) may be successively carried out without crystallization or isolation of xcex2-amino-xcex1-hydroxycarboxylic acid derivative (formula (1)). In this case, the solvent to be used is particularly preferably acetonitrile, or a mixed solvent of acetonitrile and water.
The method for obtaining an N-carbamate type protected xcex2-amino-xcex1-hydroxycarboxylic acid derivative (formula (5)) is explained in the following, wherein an amino group of xcex2-amino-xcex1-hydroxycarboxylic acid derivative (formula (1)) is protected with a carbamate type protecting group.
It is preferable to adjust the pH in the reaction system to 6-11, particularly 8-10.
As the base to adjust pH, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and triethylamine are preferably used. Alternatively, hydrochloric acid, sulfuric acid, acetic acid and citric acid are preferably used as an acid to adjust pH.
As the reaction solvent, protonic solvent such as methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, 1-butanol, water and the like, or non-protonic solvent such as acetone, 2-butanone, methylisobutylketone, toluene, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile and the like are used.
These reaction solvents may be used alone or in combination of one or more kinds thereof.
Particularly, 2-propanol or a mixed solvent of acetonitrile and water is most preferable.
The reaction is generally carried out under stirring. The reaction temperature is generally from 20xc2x0 C. to 40xc2x0 C. The reaction time is not particularly limited, but it is preferably about 10 min to 24 hrs.
After the completion of the reaction, pH is adjusted to 1.0-3.0 and the mixture is extracted with a solvent such as ethyl acetate, dichloromethane and the like to give a solution of N-carbamate type protected xcex2-amino-xcex1-hydroxycarboxylic acid.
Where necessary, moreover, the solution is concentrated, a poor solvent, such as hexane, heptane, aqueous lower alcohol solution, water and the like, is added, and crystallization yields N-carbamate type protected xcex2-amino-xcex1-hydroxycarboxylic acid.
Inasmuch as the series of reactions explained above proceed stereoselectively, the objective compound having high optical purity can be obtained in a high yield. A series of reaction schemes when the configuration of the 2-position and 3-position of N-carbamate protected xcex2-aminoepoxide of the formula (2) is (2S,3S) and (2R,3S) are exemplarily shown in the following. 
wherein A is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, each optionally having substituent(s) and optionally having heteroatom(s) in the carbon skeleton, R1 is a tert-butyl group or a benzyl group, * shows an asymmetric carbon atom, and R2 is a lower alkyl group, a benzyl group or a fluorenylmethyl group.
For a series of steps to obtain oxazolidin-2-one derivative (formula (4)) from N-carbamate protected xcex2-aminoepoxide (formula (2)), or N-carbamate type protected xcex2-amino-xcex1-hydroxycarboxylic acid derivative (formula (5)) from N-carbamate protected xcex2-aminoepoxide (formula (2)), for example, a solvent commonly used for each step, such as acetonitrile, a mixed solvent of acetonitrile and water and the like, are used, whereby each product can be subjected to successive reactions without isolation. Accordingly, the process is industrially extremely efficient.
The present invention is explained in more detail by the following Examples, which are not to be construed as limitative.